Development of novel prostate cancer therapies: Our understanding of the biology of CRPC progression has led to the discovery of more effective targeted approaches that involve modulation of the androgen-AR system. We are interested in the preclinical and clinical development of CYP17A1 inhibitors. Seviteronel (VT-464) is a novel, non-steroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. We are involved in the preclinical and clinical development of this compound. In collaboration with Dr. Donald McDonnell, we recently demonstrated that CYP17 inhibitors, with the exception of orteronel, can function as competitive AR antagonists. Conformational profiling revealed that the CYP17 inhibitor-bound AR adopted a conformation that resembled the unliganded AR (apo-AR), precluding nuclear localization and DNA binding. Further, we observed that seviteronel and abiraterone inhibited the growth of tumor xenografts expressing the clinically relevant mutation AR-F876L and that this activity could be attributed entirely to competitive AR antagonism. The results of this study suggest that the ability of CYP17 inhibitors to directly antagonize the AR may contribute to their clinical efficacy in CRPC. In collaboration with Dr. Ravi Madan (GMB, CCR, NCI), we recently completed a phase II trial of seviteronel in CRPC patients previously treated with enzalutamide and we are currently performing the PK and PD analyses for this trial. In collaboration with the University of Chicago, we recently participated in a food effect study of abiraterone for patients with CRPC and found that low-dose abiraterone acetate (with low-fat breakfast) is non-inferior to standard dosing with respect to PSA metrics. We are also interested in understanding the mechanisms of resistance of prostate cancer regimens. Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in CRPC. Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Upregulation of hypoxia inducible factor-1alpha (HIF-1a) in hypoxic tumor cells provides a mechanism of acquired resistance to current hormonal therapies and chemotherapies by increasing angiogenesis and metastasis. Given that both AR and HIF-1a are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. We demonstrated in preclinical studies that the combination of enzalutamide with HIF-1a inhibition resulted in synergistic inhibition of AR-dependent and gene-specific HIF-dependent expression and prostate cancer cell growth, suggesting a possible mechanism for overcoming enzalutamide resistance and potentiating anti-AR therapy. CRLX101 is a nanoparticle drug conjugate composed of 20(S)-camptothecin (a potent and highly selective topoisomerase I inhibitor with anti-HIF-1a properties) conjugated to a linear, cyclodextrin-polyethylene glycol-based polymer. Preclinical and clinical studies have shown CRLX101 significantly downregulates HIF-1a, impacting tumor-driven angiogenesis. The treatment combination of CRLX101 and enzalutamide provides a reasonable approach to re-sensitizing prostate cancer cells to hormonal therapy via synergistic antitumor activity and inhibition of acquired resistance. In collaboration with Dr. Madan (NCI), we are involved in a single arm pilot study to evaluate the safety and activity of combining CRLX101 with enzalutamide in patients with progressive mCRPC following prior enzalutamide treatment.